Dibenzo (c f) thiazepine (1 2) compounds

ABSTRACT

DIBENZO (C,F) THIAZEPINES (1,2) WHEREIN THE TWO BENZENE NUCLEI MAY BE SUBSTITUTED BY HALOGEN OR LOWER-ALKYL OR LOWER-ALKOXY HAVING UP TO 5 CARBON ATOMS INCLUSIVE, THE NITROGEN ATOM IS SUBSTITUTED BY LOWER-ALKYL HAVING UP TO 5 CARBON ATOMS INCLUSIVE, AND THE THIAZEPINE BEARS IN POSITION 5 AN OPTIONALLY SUBSTITUTED PIPERAZINE RADICAL OR AN OXY- OR THIO-ALKYLENEAMINO RADICAL, AND ACID ADDITION SALTS THEREOF, HAVING HYPOTENSIVE, BRONCHODILATOR AND DIURETIC ACTIVITY.

United States Patent 3,657,276 DIBENZO (c,f) THIAZEPINE (1,2) COMPOUNDSCharles Malen, Fresnes, and Michel Laubie, Vaucresson, France, assignorsto Science Union et Cie Societe Francaise de Recherche Medicale,Suresnes, France N0 Drawing. Filed Dec. 13, 1967, Ser. No. 690,091Claims priority, application Great Britain, Dec. 19, 1966, 56,720/ 66Int. Cl. C07d 93/42 US. Cl. 260-327 B 3 Claims ABSTRACT OF THEDISCLOSURE The present invention provides new dibenzo (c,f) thiazepine(1,2) compounds of the general formula in which A and B are identical ordifferent and each represents hydrogen or halogen, lower-alkylcontaining up to 5 carbon atoms, inclusive, or lower-alkoxy containingup to 5 carbon atoms, inclusive, R represents lower-alkyl containing upto 5 carbon atoms,

inclusive, Y represents (a) a piperazinyl radical of the general formula-N N--R (1 where R stands for hydrogen or a linear or branchedchainalkyl or hydro-xyalkyl radical containing up to 5 carbon atomsinclusive, a

pyrimidyl radical, an aralkyl radical such, for

example, as a benzyl or phenyl, phenethyl, or phenpropyl radical,

or a substituted aralkyl radical such, for example, as a piperonyl,anisyl, or homo-anisyl radical, said aralkyl radicals containing .up toa maximum of nine carbon atoms, or

(b) an oxyalkyleneamino or thioalkyleneamino radical of the generalformula R2 Z(CHZ)|1 -N/ R, (III) where Z represents oxygen or sulphur,

R represents lower-alkyl with up to 3 carbon atoms, inclusive, or formstogether with the nitrogen atom a hexamethyleneimine, piperidine, orpyrrolidine heterocyclic ring, and wherein n is the integer 2, 3, 4 or5.

The present invention includes in addition to the dl "ice forms of thecompounds of the general Formula I and their d and l optical isomers,the acid addition salts of these compounds derived from mineral ororganic acids. Examples of suitable mineral acids are hydrochloric,hydrobromic, isethionic, sulphuric, phosphoric and sulphamic acid.Suitable organic acids are, for example, acetic, propionic, maleic,fumaric, tartaric, citric, oxalic, benzoic, and methane sulphonic acids.

The new compounds of this invention and their physiologically tolerableacid addition salts possess valuable pharmacological and therapeuticproperties and may, therefore, be used as antihypertensive(hypotensive), vasodilatory, cardio-stimulating, bronchodilatory,respirationstimulating, diuretic, spasmolytic or antihistaminicmedicaments.

The new derivatives of the general Formula I, in which A, B and R havethe meanings defined above and wherein Y represents a piperazinylradical of the general Formula II, may be manufactured by condensing a5-chloro-l0- dioxo ll-alkyl-dibenzo (c,f) thiazepine (1,2) of thegeneral formula a in which A, B and R have the above meanings, with apiperazine of the general formula RN N-R in which R, has the abovemeaning. This condensation is advantageously carried out in an anhydrousorganic solvent such as, for example, a hydrocarbon or an ether, at atemperature ranging from 20 to C.

One form of the process for the manufacture of the compounds of thegeneral Formula I in which Y stands for a piperazinyl radical of thegeneral Formula II wherein R is a substituent other than a hydrogenatom, comprises reacting a corresponding compound in which R representsa hydrogen atom with a halogenated compound of the general formula R X(VI) where X represents a halogen atom and R, has one of the meaningsgiven above other than a hydrogen atom.

The new compounds obtained in this manner are bases which generally formwhite crystals having a sharp melting point, and in acetic acid solutionthey react with perchloric acid either as mono-basic or as di-basiccompounds. These compounds form' well-defined salts with mineral andorganic acids. However, in a strongly aqueous acid medium a certaininstability of both the base and its salts and a general tendency tosolvation of both are observed.

The new compounds of the general Formula I, in which A, B and R have theabove meanings and Y represents an oxyalkyleneamino or thioalkyleneaminoradical of the general Formula III, are obtainable by condensing aS-chloro-lO-dioxo-ll-alkyl-dibenzo (c,f) thiazepine (1,2) of the generalFormula IV with a sodium salt of a dialkylamino alcohol or adialkylaminothiol of the general formula Na --z m -N (VII) in which Z,R; and n have the above meanings. This condensation is carried out in ananhydrous organic solvent, for example, in a hydrocarbon.

The new compounds obtained in this manner are bases which are generallyoily, do not crystallize, and are soluble in aqueous mineral or organicacids. Their organic salts, on the other hand, in general form welldefined crystals, but when melted they decompose. These salts can bedetermined with perchloric acid in an acetic acid medium. The5-chloro-10'dioxo-1l-alkyl-dibenzo (c,f) thiazepine (1,2) of the generalFormula IV, which is used as starting material for the synthesesreferred to above, belongs to a new heterocyclic system based on thenucleus of 5-H,1l-H-dibenzo (c,f) thiazepine (1,2). All compoundsstemming from this basic nucleus are, therefore, new. This isparticularly true of 5-chloro-l0-dioxo-1l-alkyl-dibenzo (c,f) thiazepine(1,2) of the general Formula IV, which has been obtained by thefollowing route:

An ortho-carbomethoxybenzene sulphochloride of the general formula "oocu(VIII) in which B has the above meanings, prepared by the method of H.Meerwein et al. [Berichte 90, pages 841-852 (1957)] or by the method ofUS. Pat. 2,667,503, is con densed in an aqueous alkaline orhydroalcoholic medium or in a tertiary organic base with anN-monoalkylaniline which is substituted and corresponds to the generalformula \N li/ A (where R and A have the above meanings) to form acompound of the general formula According to another form of the processfor the manufacture of compounds of the Formula X, a compound of theFormula X, in which 'R represents a hydrogen atom, is reacted with aconventional alkyl halide.

The methyl ester of the general Formula X is first transformed byhydrolysis into a carboxylic acid and then into the acid chloride bymeans of a chlorinating agent, for example thionylchloride in ahydrocarbon. 'Ihis acid chloride is cyclized in an inorganic or organicsolvent (for example, in carbon disulphide, methylene chloride orbenzene) by means of a conventional cyclizing agent, such, for example,as aluminum chloride, to give rise to a new compound,-dioxo-1l-alkyl-dibenzo (c,f) thiazepine (1, 2)-5-one, of the generalformula EXAMPLE 1 10-dioxo-1l-methyl-dibenzo (c,f) thiazepine(1,2)-5-one (Ii b Methyl ester (1).--234.5 grams ofortho-carbomethoxybenzene sulphochloride (melting point 64-65 C. (BK))are gradually added to a solution of 115 grams of N-methylaniline in 300ml. of pyridine. From the start of this addition a deep red colorationdevelops. On completion of the addition the reaction mixture is heatedfor minutes at C.

While still hot, the reaction product is poured over 2 kg. of ice. Aftersuction filtering and washing with water, there are obtained 287 gramsof a crude product melting at to 92 C. (BK).

After recrystallization from 0.5 liter of ethanol, there are obtained263 grams of a pure product melting at to 92 C. (BK).

Acid (2).The methyl ester thus obtained is suspended in 0.5 liter ofabsolute ethanol and a solution of 59 grams of potassium hydroxide in200 ml. of water is added.

The whole reaction mixture is then refluxed for 90 minutes, cooled, oneliter of water is added, and the mixture is acidified to pH=1 andextracted with ether.

The ethereal solutions are washed with water, dried, and concentrated toyield 212 grams of a crude acid melting at 80 to 84 C. (BK). This acidmay be conveniently recrystallized from cyclohexane, although it isequally suitable for the following synthesis as it is obtained.

Acid chloride (3).l5.75 grams of the above acid are dissolved withheating in 60 ml. of benzene. In the course of 15 minutes, 8.8 ml. ofthionylchloride are added and the mixture is refluxed for two hours. Theresulting clear solution is evaporated to dryness with exclusion ofhumidity. The residue comprises the crude acid chloride, which isdissolved in ml. of anhydrous carbon disulphide, to which, whileagitating the whole reaction mixture well while keeping out moisture, 20grams of powdered aluminum chloride are added in portions.

The reaction is slightly exothermic. Fifteen minutes after completion ofthe addition of aluminum chloride, the mixture is heated to reflux andthus maintained for one hour. After cooling, the solvent is decanted,whereafter the residue is hydrolysed with 200 grams of ice and extractedwith chloroform. The organic layers are washed with dilute hydrochloricacid, then with Water, then with soda solution, and finally with water.

The whole reaction product is dried and the solvent evaporated. Theresidue yields, on recrystallization from 320 ml. of absolute ethanol,9.5 grams of 10-dioxo-l1- methyl-dibenzo (c,f) thiazepine (1,2)-5-one,which melts with sublimation at 157 to 158 C. (MK). The structure ofthis compound has been established by its infrared spectrum and thenuclear magnetic resonance spectrum.

The infrared spectrum of IO-dioxo-ll-methyl-dibenzo (c,f) thiazepine(1,2)-5-one, in a suspension in a mineral oil mull (NujolTM), on Perkin221 (TM) infrared spectrometer, shows a carbonyl band at 1650 cm."

and the symmetrical and asymmetrical frequency bands of S at 1185 cmrand 1340 cm.-

The nuclear magnetic resonance spectrum of 10-dioxoll-methyl-dibenzo(c,f) thiazepine (1,2)--one shows a singlet at 3.3 ppm. corresponding tothree protons (PI-CH and a double complex pattern between 7 and 8p.p.m., corresponding to two groups of 4 aromatic protons.

The following compounds were obtained by the same process:

(a)dioxo 11 ethyl-dibenzo (c,f) thiazepine (1,2)-5- one, melting at163-164 C. (MK) with sublimation.

(b) 1-chloro-10-dioxo-1l-methyl-dibenzo (c,f) thiazepine (1,2)-5-one,solvated with. a benzene molecule, melting at 147-150 C. (MK).

(c) 2-chloro-10-dioxo-l'l-methyl-dibenzo (c,f) thiazepine (1,2)-5-one,melting at l53154 C. (MK).

(d) 3-chloro-10-dioxo-l1-methyl-dibenzo-(c,f) thiazepine (1,2)-5-one,melting at 19l192 C. (BK).

(e) Z-methoxy-lO-dioxo 11 methyl-dibenzo (c,f) thiazepine (1,2)-5-one,melting at 170172 (BK) with sublimation.

(f) 3-methoxy dioxo 11 methyl dibenzo (c,f) thiazepine (1,2) 5 one,melting at 150 to 153 C. (BK).

(g) 4-methoxy-10-dioxo 11 methyl-dibenzo (c,f) thiazepine (1,2)-5-one,melting at 224 to 225 C. (BK) with sublimation.

(h) 4-hydroxy 10 dioxo 11 methyl dibenzo (c,f) thiazepine (1,2) 5 one,melting at 156 to 157 C. (BK).

(i) 10 dioxo 11 11. propyl-dibenzo (c,f) thiazepine (1,2)-5-one, meltingat 1131l4 C. (MK).

(3') 8-chloro-10-dioxo-1l-methyl-dibenzo (c,f) thiazepine (1,2)-5one,melting at 174-175 C. (MK).

(k) 7-chloro-10-dioxo-1l-methyl-dibenzo (c,f) thiazepine (1,2)-5-one,melting at 162-163 C. (BK).

(l) 2,8-dichloro10-dioxo 11 methyl-dibenzo (c,f) thiazepine (1,2)-5-onemelting at 197-200 C. (MK). (m) 3,8-dichloro 10 dioxo 11 methyl-dibenzo(c, f)

thiazepine (1,2)-5-one, melting at 19l-193 C. (MK).

EXAMPLE 2 10-dioxo-1l-methyl-dibenzo (c,f) thiazepine (1,2)-5-0] CH J...

Three hundred mg. of sodium borohydride are gradually added to anagitated suspension of 1.36 grams of lO-dioxo-ll-methyldibenzo (c,f)thiazepine (1,2)-5-one in 5 ml. of methanol. The agitation is continuedfor 45 minutes after completion of the addition, and the batch is thenheated at reflux for one hour, diluted with 20 ml. of water, and thereaction product suctioned off, washed with water, dried andrecrystallized from 8 ml. of normal propanol, to yield 1.15 gram of10-dioxo-l1-methyl-dibenzo (c,f) thiazepine (1,2)-5-01, melting at 138to 140 C. (MK).

The structure of this compound has been determined by its infra-red andnuclear magnetic resonance spectra. The infra-red spectrum of IO-dioxo-ll-methyl-dibenzo (c,f) thiazepine (1,2)-5-01, suspended in a mineral oilmull (Nujol-TM), on a Perkin 221 (TM) infra-red spectrometer, contains anarrow and substantial band attributable to the hydroxyl function at3485 cm? and a very attenuated band corresponding to the vibration of S0The nuclear magnetic resonance spectrum of 10-dioxoll-rnethyl-dibenzo(c,f) thiazepine (1,2)-5-01 contains a singlet at 3.2 p.p.m.corresponding to three protons (NCH doublet at 4.4 to 4.6 ppm,corresponding to the proton CH, a second doublet at 5.9 to 6.1 ppm,corresponding to the hydroxyl proton, and a double complex patternbetween 7.2 and 8 p.p.m. corresponding to 8 aromatic protons.

By the same process the following were prepared:

(a) lO-dioxo-ll-ethyl-dibenzo (c,f) thiazepine (1,2)-5- ol, melting at126 to 127 C. (MK).

(b) 2-chloro-10-dioxo-1l-methyl-dibenzo (c,f) thiazepine (1,2)-5-ol,melting instantaneously at C. (BK).

(c) 3-chloro-10-dioxo-1l-methyl-dibenzo (c,f) thiazepine (1,2)-5-ol,melting at 138 to 143 C. (BK).

(d) 2-methoxy-10-dioxo-1l-methyl-dibenzo (c,f) thiazepine (1,2)-5-01,melting at 145 to 146 C. (BK).

(e) 4methoxy-l0-dioxo-1l-methyl-dibenzo (c,f) thiazepine (1,2)-5-ol,melting at 179 to 182 C. (BK).

(f) 10-dioxo l1-n.propyl-dibenzo (c,f) thiazepine (1,2)-

5-01 (oil) (g) 8-chloro-10 dioxo-1l-methyl-dibenzo (c,f) thiazepine(1,2)-5-ol, melting at 197.5 to 200 C. (MK).

(h) 7-chloro-10-dioxo-ll-methyl-dibenzo (c,f) thiazepine (1,2)-5-01,melting at 191-193 C. (BK).

(i) 2,8-dichloro-10-dioxo-1l-methyl-dibenzo (c,f) thiazepine (1,2)-5-ol,melting at 160165 C. (BK).

(j) 3,8-dichloro-10-dioxo-1l-methyl-dibenzo (c,f) thiazepine (1,2)-5-ol,melting at 189-l92 C. (MK).

EXAMPLE 3 5 -chloro-1 0-dioxo-1 l-methyl-dibenzo (c,f) thiazepine (1,2)

l. so -jg A solution of six grams of 10-dioxo-ll-methyl-dibenzo (c,f)thiazepine (1,2)-5-01 in 30 ml. of chloroform is saturated at 15 C. orbelow with hydrochloric gas. The whole reaction mixture is further keptin contact with HCl for 15 minutes, and the solvent is then evaporated.The residue is recrystallized from 80 ml. of 1,2-dichloroethane, toyield 4.7 grams of 5-chloro-10-dioxo-1l-methyldibenzo (c,f) thiazepine(1,2), which melts at 242 to 244 C. (BK) with sublimation anddecomposition.

dl-5-[4-methyl) piperazin-1-yl]-10-dioXo-1l-methyldibenzo (c,f)thiazepine (1,2)

N-methylpiperazine (5.94 grams) in 10 ml. of anhydros nitromethane isadded dropWiSe with agitation to a suspension of 8.8 grams ofS-chloro-lO-dioxo-ll-methyldibenzo (c,f) thiazepine (1,2) in 50 ml. ofanhydrous nitromethane. The ensuing reaction is slightly exothermic andthe temuperature rises to 32 C. On completion of this exothermicreaction, the batch is heated for 30 minutes at 50 C. and is thenevaporated to dryness under vacuum.

The residue is taken up with 25 ml. of Water and then with 15 ml. ofN-hydrochloric acid, heated to boiling, filtered, and the filtrate iscooled and suctioned to yield 9 grams of the monohydrochloride ofdl-5[(4'-methyl) piperazin-1'-yl]-10-dioxo-1l-methyl-dibenzo (c,f)thiazepine (1,2), melting with sublimation at 250260 C. (BK). These 9grams of monohydrochloride can be recrystallized from 50 ml. of water.Yield: 70%.

When a specimen of this hydrochloride is treated with sodium carbonate,it furnishes the corresponding base in the form of white crystals whichcan be recrystallized from benzene and which melt at 215 to 218 C. (BK).

By the same process the following were produced:

(a) dl-S [(4' piperonyl) piperazinl yl]-10-dioxo-11- methyl-dibenzo(c,f) thiazepine (1,2), whose monohydrochloride melts instantaneously at260 C. (BK).

(b) dl-5-[(4-ethyl) piperazin-1'-yl]-10-dioxo-ll-methyldibenzo (c,f)thiazepine (1,2), whose monohydrochloride decomposes above 231 C. (BK).

(c) dl-3-chloro-5[(4'-methy1) piperazin-l'-yl]-10-dioxoll-methyl-dibenzo(c,f) thiazepine (1,2), melting at 228.5229.5 C. (MK), and Whose acidmaleate melts instantaneously at 185 C. (BK) with decomposition.

(d) dl-2-chloro-5-[ (4'-methyl) piperazin-1'-yl]-l-dioxoll-methyl-dibenzo (c,f) thiazepine (1,2), melting at 238 to 240C. (MK).

(6) dl--[(4'-buty1) piperazin -1-yl]-l0-dioxo-l1-methy1- dibenzo (c,f)thiazepine (1,2), melting at 156l57 C. K).

(f) dl-2-chloro-5-[(4-ethyl) piperazin-1'-yl]-10-dioxoll-methyl-dibenzo(c,f) thiazepine (1,2), melting at 21 8-222 C. (BK).

(g) dl-5-[(4-pyrimid-2"-yl) piperazin-1'-yl]-10-dioXoll-methyl-dibenzo(c,f) thiazepine (1,2), melting at 234236 C. (BK).

(h) dl-5-[(4'-methyl) piperazin-l'-yl]-l0-dioxo-1l-ethyldibenzo (c,f)thiazepine (1,2), melting at 198199 C (BK).

(i) dl 5 [(4' beta-hydroxyethyl) piperazin 1' yl]- dioxo 11methyl-dibenzo (c,f) thiazepine (1,2), which melts instantaneously at194 C. (BK).

(j) dl 5 [(4' ben'zy1) piperazin -1' yl] 10 dioxo- 11 methyl-dibenzo(c,f) thiazepine (1,2), melting at 158161 C. (MK).

(k) dl 5 [(4' methyl) piperazin 1' yl]-IO-dioxo- 11-n.propyl-dibenzo(c,f) thiazepine (1,2) whose acid maleate melts instantaneously at 218C. with decomposition.

(1) dl-5-[(4' methyl) piperazin 1' yl] 8 chloro- 10 dioxo 11methyl-dibenzo (c,f) thiazepine (1,2), whose acid maleate melts at185-188 C. (BK).

(m) dl-S-(piperazin l' yl) 8 chloro l0 dioxo- 11 methyl-dibenzo (c,f)thiazepine (1, 2), whose acid maleate melts at 180 C. (BK) withdecomposition.

(n) dl-3,8-dichloro 5 [(4' methyl) piperazine-1- yl] 10 dioxo 11methyl-dibenzo (c,f) thiazepine 1,2), whose acid maleate meltsinstantaneously at 190 C. (BK) with decomposition.

(o) dl-5-[(4' methyl) piperazin 1' yl] 7 chloro- 10 dioxo l1methyl-dibenzo (c,f) thiazepine (1,2), whose acid maleate meltsinstantaneously at 240 C. with decomposition.

(p) dl-2,8-dichloro 5 [(4'-methyl) pipernzin-l ylll0 dioxo 11methyl-dibenzo (c,f) thiazepine (1,2), whose acid maleate meltsinstantaneously at 160 C (BK) with decomposition.

8 EXAMPLE 5 d [-5 -piperazin-1 -yl- 10-dioxo-1 l-methyl-dibenzo (c,f)thiazepine (1,2)

With vigorous agitation, 12.9 grams of solid 5-chloro-10-dioxo-1l-methyl-dibenzo (c,f) thiazepine (1,2) in the pulverulentstate are added at 60 C. portionwise to a solution of 18.8 grams ofanhydrous piperazine in ml. of dry benzene and, after completion ofaddition, the batch is agitated for another hour and then evaporated todryness. The residue is taken up with 200 ml. of water and 20 ml. ofconcentrated hydrochloric acid. A small quantity of undissolved matteris filtered off, and the acid filtrate is treated with sodium hydroxide.The precipitate is suctioned off, washed with water and then dried invacuo, to yield 11.35 grams of dl-5-piperazin 1' yl-l0-dioxo-ll-methyl-di-benzo (c,f) thiazepine (1,2) in the crude state,which melts at 162-l83 C. (BK) and, after recrystallization from 25 ml.of absolute ethanol, yields 9.4 grams of base in the pure state meltingat 182 to 184 C. (KB). The acid maleate corresponding to this base isprepared by mixing a solution of 2.89 grams of the above base in 13 ml.of ethanol with a solution of 1.04 grams of maleic acid in 3 ml. ofethanol and refluxing this mixture for 3 minutes. The reaction mixtureis kept overnight in the refrigerator and the crystalline salt is thensuctioned oif, dried, and recrystallized from ethanol, to yield 2.7grams of the solid maleate of dl-5-piperazin l yl 10 dioxo 11methyl-dibenzo (c,f) thiazepine (1,2), which melts instantaneously at C.(BK).

EXAMPLE 6 dl-5-[(4beta-hydroxyethyl) piperazin-l-yl]-10-dioxo-ll-methyl-dibenzo (c,f) thiazepine (1,2)

A well-agitated suspension of 6.8 grams of al-5-piperazin 1 yl 10 dioxo11 methyl-dibenzo (c,f) thiazepine (1,2), 7 grams of dry sodiumcarbonate, and 1.5 gram of sodium iodide in 100 ml. of anhydrous acetoneis mixed under reflux with a solution of 4 grams of chloroethanol in 20ml. of anhydrous acetone.

The reflux temperature is maintained for 4 hours after completion ofaddition, and the batch is then evaporated to dryness under vacuum. Theresidue is washed with Water and then extracted with chloroform. Thechloroform solution is extracted with dilute hydrochloric acid. The acidwaters are rendered alkaline with sodium hydroxide. The base isextracted with chloroform. The chloroform extract is washed, dried andevaporated. The oily residue is dissolved in boiling ethyl acetate,allowed to crystallize overnight, and then suction-filtered, to yield4.2 grams of dl-[(4'-beta-hydroxyethyl) piperazin-1'- yl] dioxo 11methyl-di benzo (c,f) thiazepine 1,2), which melts instantaneously at194 C. (BK).

EXAMPLE 7 dl-S- (2'-diethylamino-oxyethyl)-10-dioxo-1 1- methyl-dibenzo(c,f) thiazepine (1,2)

A solution of 5.85 grams of diethylaminoethanol in 10 ml. of dry tolueneis added dropwise to a suspension of 6 grams of sodium hydride in a oilysuspension di- 20 luted with 20 ml. of anhydrous toluene, whilemaintaining the temperature between 0 and 5 C. The whole reactionmixture is then allowed to warm to room temperature with exclusion ofmoisture, whereafter 12.9 grams of 5- chloro-lO-dioxo-ll-rnethyl-dibenzo (c,f) thiazepine (1,2) are added dropwise.

After completion of addition, the batch is refluxed for minutes and thenevaporated to dryness under vacuum. The residue is taken up in 70 ml. ofN hydrochloric acid and the insoluble matter filtered off. The acidaqueous 30 solution is treated with carbon black, filtered, and thefiltrate rendered alkaline. The oily base is extracted with ether andthe organic layer washed with water, dried, and then evaporated to yield9 grams of a crude, thick oil. Four grams of this oil are dissolved in10 ml. of hot ethanol and mixed with 1.27 gram of fumaric acid in 25 ml.of hot ethanol. The whole reaction mixture is refluxed for 5 minutes,evaporated to dryness, and the residue crystallized from a mixture ofacetone and ether, and recrystallized from ethanol to yield 2.65 gramsof the acid fumarate of dl-S-(2-diethylaminooxyethyl)-10-dioxo-l1-methyldibenzo (c,f) thiazepine 1,2), which crystallizes with onemolecule of ethanol and melts instantaneously at 100 to 105 C. (BK).

The following compounds were prepared by the same process:

(a) dl-S- (2'-dimethylamino-oxyethyl)-l0-dioxo-1 l-methyl-dibenzo (c,f)thiazepine (1,2), whose acid maleate melts instantaneously at 154 C.(BK), and whose iodomethylate hemihydrate decomposes around 150 C.

(b) dl-S-(3'-dimethylamino-oxypropyl) 10 dioxo-11- methyl-dibenzo (c,f)thiazepine (1,2), whose acid maleate melts instantaneously at 140 C.(BK).

(c) dl-5 (5 dimethylamino-oxyamyl) 10 dioxo-l1- methyl-dibenzo (c,f)thiazepine (1,2).

((1) a'l-S-(2'-hexamethyleneamino-oxyethyl) 10 dioxoll-methyl-dibenzo(c,f) thiazepine (1,2).

(e) dl-5-(3-piperidino oxypropyl) 10 dioxo-1 1methyl-dibenzo (c,f)thiazepine (1,2).

(f) dl-S-(2'-pyrrolidino-oxyethyl) 10 dioxo-ll-methyldibenzo (c,f)thiazepine (1,2).

EXAMPLE 8 dl-2-methoxy-5-(2'-dimethylamino-thioethyl) 10dioxoll-methyl-dibenzo (c,f) thiazepine (1,2)

Three grams of dimethylamino-ethanethiolhydrochloride are added to asolution of 1 gram of sodium in ml. of absolute ethanol.

While agitating the resulting suspension, there are added portionwise6.48 grams of 2-methoxy-5-chloro-l0- dioxo-ll-methyl-dibenzo (c,f)thiazepine (1,2), keeping the temperature between 15 and 20 C. At theend of the addition, the whole reaction mixture is refluxed for 30minutes, then evaporated to dryness under vacuum, and the residue takenup in ml. of N/2 hydrochloric acid.

The hydrochloric acid solution is filtered and extracted with ether. Theaqueous phase is rendered alkaline and the oil extracted with ether. Theethereal solutions are washed with water, dried and evaporated.

The crystalline residue consists of dl-2-methoxy-5-(2'-dimethylaminothioethyl) 10 dioxo 11 methyl-dibenzo (c,f) thiazepine(1,2), of which a sample on recrystallization from a mixture of ether,cyclohexane and benzene melts at 97*100 C. (MK).

A sample of 3.43 grams of the above crude base are dissolved in 7 ml. ofethanol and mixed with 1.04 gram of maleic acid in 7 ml. of ethanol. Themixture is refluxed for 5 minutes and then kept overnight in an icebox.After suctioning, drying and recrystallization from a mixture of 15 ml.of ethanol and 0.5 ml. of water, there are obtained 3.3 grams of theacid maleate of dl-Z-methoxy-S-(2-dimethylaminothioethyl) 10dioxo-ll-methyl-di benzo (c,f) thiazepine (1,2), which meltsinstantaneously at 166 C. (BK).

The following were produced by the same process:

(a) dl-5-(2'-dimethylamino thioethyl) 10 dioxo-11- methyl-dibenzo (c,f)thiazepine (1,2), whose acid maleate melts at l48152 C. (BK).

(b) dl-2-chloro-5-(2-dimethylamino-thioethyl) 10 dioxo-ll-methyl-dibenzo(c,f) thiazepine (1,2), whose acid maleate melts instantaneously at 147to 148 C. (BK).

(c) dl-5-(2' diethylamino thioethyl) 10 dioxo11- methyl-dibenzo (c,f)thiazepine (1,2), whose acid maleate melts instantaneously at 146 C.(BK).

(d) dl-2-chloro-5-(2-diethylamino thioethyl)-10-dioxoll-methyl-dibenzo(c,f) thiazepine 1,2), whose acid fumarate melts instantaneously at 190C. (BK).

(e) dZ-Z-methoxy 5 (2 diethylamino thioethyl)-10-dioxo-11-methyl-dibenzo (c,f) thiazepine (1,2), whose acid maleate meltsinstantaneously at C. (BK).

(f) a'l-5-(2 dimethylamino-thioethyl) 10 dioxo-11- methyl-dibenzo (c,f)thiazepine (1,2), whose acid maleate melts instantaneously at 150 C.(BK).

(g) dl-5-(2'-dimethylamino thioethyl) 8 chloro-lO-dioxo-ll-methyl-dibenzo (c,f) thiazepine (1,2), whose acid maleate meltsinstantaneously at 150 C. (BK) with decomposition.

(h) dl-S-(2-dimethylamino-thioethyl) 7 chloro-lO-dioxo-ll-methyl-dibenzo(c,f) thiazepine (1,2), whose hydrochlorate melts instantaneously at 250C. (BK) with decomposition.

(i) dl-2,8-dichloro 5 (2' dimethylamino thioethyl)- 10-dioxo 11 methyldibenzo (c,f) thiazepine (1,2), whose hydrochlorate meltsinstantaneously at C. (BK) with decomposition.

(j dl-3,8-dichloro 5 (2 dimethylamino thioethyl)- 10-dioxo-l1-methyldibenzo (c,f) thiazepine (1,2), whose hydrochlorate melts at 160 C. withcrystallization, and at 230 C. (BK) (water) with decomposition.

(k) dl-3,8-dichloro 5 (2 dimethylamino thioamyl)-10-dioxo-ll-methyl-dibenzo (c,f) thiazepine (1,2).

(1) dl-3,8-dichloro 5 (2'-dimethylamino thiopropyl)-10-dioxo-1l-methyl-dibenzo (c,f) thiazepine (1,2).

The pharmacological study of the new compounds and their physiologicallyacceptable salts gives the following results:

The LD studied by peroral administration in mice varies from 450 to5,000 mg./ kg. and from 250 to 2,000

1 1 mg./kg. by intraperitoneal administration for the differentcompounds.

Administered at a dose of 5 mg./kg. i.v. in the anesthetized dog, thecompounds provoke a prolonged decrease of the blood pressure from to 100mm. Hg for more than minutes.

At the same dose, the new compounds are able to inhibit the bronchospasmof the guinea-pig provoked by histamine, serotonine and acetylcholine.

A very pronounced diuretic action can be demonstrated in dogs with dosesfrom 30 to 90 mg./ kg. p.o. The increase of the urinary volume variesfrom 20 to 120%, with a corresponding increase of the elimination of theelectrolytes.

The new compounds may be used in therapy, especially in the treatment ofhypertension, hydroelectrolytic retention and bronchospasms. They can beadministered in various pharmaceutical forms in association withdifferent pharmaceutical solid or liquid carriers such, for example, asdistilled water, lactose, talc, glucose, gum-arabic or ethyl cellulose.The doses may advantageously vary from to 500 mg. in parenteral, rectalor oral administration.

Where the foregoing examples produce a compound having a methyl or otherlower-alkyl group, it is to be understood that compounds containingother lower-alkyl groups of straight or branched nature and containingup to five carbon atoms inclusive, such as methyl, ethyl, propyl,isopropyl, butyl, see-butyl, t.-butyl, amyl, and isoamyl, are preparedin the same manner by substitution in the process of the appropriatedifferent lower-alkyl starting material. Hydroxylower-alkyl radicals maycarry primary, secondary, or tertiary hydroxyl groups and have the samecarbon atom limit action as lower-alkyl. Likewise, where chloro or otherhalogen atom is present, although chlorine is preferred, further halogencompounds including iodo, bromo, chloro, and fluoro compounds areprepared starting from the appropriate halogenated starting material.Similarly, where methoxy or other loWer-alkoxy group is present,compounds having other lower-alkoxy groups containing variouslower-alkyl groups having up to five carbon atoms inclusive are preparedin the same manner from the appropriate different lower-alkoxy startingmaterial. Moreover, when one dilower-alkylamino group, such as thedimethylamino group, is present in a compound, other dilower-alkylaminocompounds are prepared in the same manner starting only with theselected different diloweralkylamino compound. In the same manner, orthoand meta substituted products are produced instead of the para byutilizing the selected ortho or meta substituted starting material, andvice versa. Similarly, other molecular changes within the scope of theinvention are readily made.

The compounds of the invention are generally characterized by thepharmacological activity hereinbefore stated, making them useful incounteracting certain pathological abnormalities in a living animalbody. Effective quantities of the pharmacologically active compounds ofthe invention may be administered to a living animal body in any one ofvarious ways, for example, orally as in capsules or tablets,parenterally in the form of sterile solutions, suspensions, or by pelletimplantation, and in some cases intravenously in the form of sterilesolutions, Other modes of administration are cutaneously,subcutaneously, bucally, intramuscularly, and intraperitoneally.

As representative of living animal bodies which may be treated with thecompounds and compositions of the invention, and according to the methodof treating of the invention, for alleviation of the same and/or similarconditions as those described, may be mentioned the following: domesticanimals such as dogs and cats, farm animals such as horses, cows, sheep,and goats, fur-bearing animals such as mink, seal, muskrat, fox,raccoon, ermine, and weasel, and 200 animals such as bears, raccoons,foxes, monkeys, baboon, and the like.

Pharmaceutical formulations are usually prepared from a predeterminedquantity of one or more of the compounds of the invention, preferably insolid form. Such formulations may take the form of powders, elixirs,solutions, pills, capsules, pellets or tablets, with or without, butpreferably With, any one of a large variety of pharmaceuticallyacceptable vehicles or carriers. When in admixture with a pharmaceuticalvehicle or carrier, the active ingredient usually comprises from about0.01 to about percent, normally from about 0.05 to about 15 percent, byweight of the composition. Carriers such as starch, sugar, talc,commonly used synthetic and natural gums, Water, and the like, may beused in such formulations. Binders such as gelatin, and lubricants suchas sodium stearate, may be used to form tablets. Disintegrating agentssuch as sodium bicarbonate may also be included in tablets.

Although relatively small quantities of the active materials of theinvention, even as low as 0.1 milligram, may be used in cases ofadministration to subjects having a relatively low body weight, unitdosages are usually five milligrams or above and preferably twenty-five,fifty, or one-hundred milligrams or even higher, depending of courseupon the subject treated and the particular result desired, as will beapparent to one skilled in the art. Broader ranges appear to be one to500 milligrams per unit dose. The active agents of the invention may becombined for administration with other pharmacologically active agents,such as analgesics, sedatives, tranquilizers, steroids or hormones, orthe like, or with buffers, antacids or the like, and the proportion ofthe active agent or agents in the compositions may be varied widely. Itis only necessary that the active ingredient of the invention constitutean effective amount, i.e., such that a suitable effective dosage will beobtained consistent with the dosage form employed. Obviously, severalunit dosage forms may be administered at about the same time. The exactindividual dosages as well as daily dosages in a particular case will ofcourse be determined according to wellestablished medical and/ orveterinary principles.

For example, the compound dl-5-[(4'-methyl) piperazin1'-yl]-10-dioXo-1l-methyl-dibenzo (c,f) thiazepine (1,2), after chronictoxicity studies in laboratory animals, which showed a sufficient safetyand no toxic effects on the organs, was administered perorally 2-3t.i.d. in mg. capsules to human patients suffering from asthmabronchiale during 15 days. All the patients showed a good therapeuticeffect manifesting itself in an improvement of the respiration with goodtolerance and no side effect. In 9 healthy volunteers, 200 mg. p.o. ofthe same product were able to inhibit bronchospasm provoked byinhalation of acetyl cholin.

wherein A represents a member selected from the group consisting ofhydrogen, chloro, and methoxy, and R is lower alkyl having up to 5carbon atoms, inclusive.

13 2- The compound of claim 2 which is S-ch1oro-10-dioxo-ll-methyl-dibenzo (c,f) thiazepine (1,2).

3. The compound of claim 2 which is 2 methoxy, 5 chlor0-10 dioxo-llmethyl-dibenzo (c,f) thiazepine (1,2

References Cited UNITED STATES PATENTS 14 3,422,106 1/1969 Boissier eta1. 260268 X 3,519,633 7/1970 Weber et a1. 260-327 X 3,542,790 11/1970Weber et al. 260-268 X 5 DONALD G. DAUS, Primary Examiner US. Cl. X.R.

260-2564 R, 268 TR, 293.46, 326.81; 424258, 275

